Major depressive disorder (MDD) is a serious and recurrent illness and a leading cause of disability. Though treatments are available, these often take weeks to months to exert their effect, and some people only respond partially or do not respond at all. To guide more effective, faster acting and personalized treatment strategies in the clinical setting, there is thus an important need to identify biological markers predictive of rapid therapeutic response. To advance discovery in this area, this K24 proposal includes mentorship, career development and research aims that build onto the goals of our NIH-funded R01 (MH092301), which is focused on using advanced neuroimaging methods to detect different aspects of treatment-related brain plasticity in MDD. Electroconvulsive therapy (ECT), which is currently the most effective acute treatment for severe MDD and which involves direct action on the central nervous system, is used as the R01 treatment modality. Since a combination of biological markers may better characterize the mechanisms and predictors of treatment response, as a recent adjunct to our R01, we are also examining peripheral lymphocyte gene expression to more comprehensively address the biological bases of rapid therapeutic response to ECT. Producing a clinical response within hours, the NMDA receptor antagonist, ketamine, has recently emerged as a novel pharmacologic agent for depression treatment with a response rate comparable only to ECT. To obtain a greater understanding of the biological processes underlying fast-acting therapies and to confirm basic science findings implicating glutamatergic pathways, the candidate's K24 Research Plan is to identify imaging and gene expression markers of therapeutic response to ketamine treatment. To target overlapping rapid response mechanisms, by leveraging data from our R01 project, candidate markers of response to ketamine and ECT will be compared. Novel imaging methods applied in a subsample of ketamine patients will provide further opportunity to explore treatment-related neuroplasticity localized to dorsal and/or ventral fronto-limbic networks. To allow the candidate to better design and lead clinical studies incorporating interdisciplinary approaches to investigate and compare mechanisms of rapid antidepressant action, the candidate's Career Development Plan is to develop knowledge and/or new skills in the field of genomics and in the pharmacological basis of antidepressant treatments for MDD as well as also hone existing skills in neuroimaging. In line with the candidate's area of expertise in imaging and clinical neuroscience, the Mentoring Plan will provide theoretical and hands-on training to mentees in clinical imaging applications directed towards the longitudinal investigation of treatment mechanisms in MDD and potentially in other psychiatric conditions, and the skills to successfully incorporate imaging methods into patient-oriented research (POR) programs that will lead to future independent funding. The candidate's research and career development aims, which are both complementary and unique to our funded R01, will provide a rich basis for training while furthering POR in a critical area.